This invention relates to 3-methylene substituted androst-4-ene-17-oxygenated compounds substituted with various substituents at the 10.beta.-position, to their use as inhibitors of estrogen biosynthesis, and to therapeutically useful compositions containing these valuable compounds. The invention also includes within its scope analogous androstene derivatives unsaturated at the 1,2- and/or 6,7-positions. It includes also certain novel intermediates useful for the preparation of the biologically active compounds.
In recent years the mechanism of estrogen biosynthesis has been elucidated. It proceeds via the transformation of the C-19 neutral steroids to the C-18 phenolic estrogens. The aromatization reaction involves expulsion of the angular C-19 methyl group as formic acid and the stereospecific loss of the C-1 and C-2 hydrogens. A complex of microsomal enzymes referred to as aromatase is responsible for these transformations. As this mechanism became understood, the opportunity was presented for designing compounds which would retard the synthesis of estrogen by interfering with the action of aromatase. Such compounds are known as aromatase inhibitors.
Although biosynthesis of estrogen occurs principally in the ovaries and testes, some also occurs in adipose tissue and muscle as well as other tissues. This peripheral aromatization of androgens to estrogens increases after menopause and becomes the main source of estrogens in women. Peripheral aromatization may similarly increase after ovariectomy which is frequently performed for the treatment of breast cancer. Some breast tumors themselves are also reported to synthesize estrogens. In endometrial cancer, peripheral formation of estrogen appears to be important in the etiology of the disease. Thus, inhibition of estrogen production by compounds which could act at all aromatizing sites might be an effective alternative to surgical removal of ovaries and adrenals in patients with breast cancer and a useful treatment for endometrial cancer.
The aromatase inhibitors could also be useful in the treatment of other estrogen related phenomena such as fertility control, gross ceptic disease and benign prostatic hypertrophy.
U.S. Pat. No. 4,235,893 describes certain ester derivatives of 4-hydroxy-4-androstene-3,17-dione as useful for the inhibition of estrogen biosynthesis. U.S. Pat. No. 4,322,416 describes certain 1-alkynyl steroids as aromatase inhibitors.
Other aromatase inhibitors such as ammoglutethimide and cyanoketone are also known, but these compounds interfere with the action of a broad spectrum of enzymes involved in the production of other essential steroid hormones. These steroids must be replaced when such conventional aromatase inhibitors are employed in therapy.